Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial

SummaryBackground Approximately 40% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) are not cured with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone). We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas. Methods frontMIND is a phase 3, randomised, double-blind, placebo-controlled study conducted at 298 centres in North America, South America, Europe, and the Asia–Pacific region. Patients aged 18–80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m2 intravenous on day 1, cyclophosphamide 750 mg/m2 intravenous on day 1, doxorubicin 50 mg/m2 intravenous on day 1, vincristine 1·4 mg/m2 maximum 2 mg intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1–5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1–10), while those in the R-CHOP group received matching placebos. The primary endpoint was investigator-assessed progression-free survival (defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treat population; safety was included as a secondary endpoint among all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling. Findings Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group. At the time of primary analysis (median follow-up 35·2 months 95% CI 35·0–35·4), progression-free survival was improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio HR 0·75 95% CI 0·59–0·96; p=0·0194), with 2-year progression-free survival rates of 71·1% (66·3–75·4) with tafa-len-R-CHOP versus 62·9% (57·9–67·5) with R-CHOP. Interim HR for overall survival was 0·85 (0·63–1·14). The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 87% of 443) than with R-CHOP (340 76% of 447). Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 6%) than with R-CHOP (17 4%). However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 19% vs 97 22%). Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 16% of 443) and R-CHOP group (66 15% of 447). Interpretation Progression-free survival was significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide. Overall survival data are immature; follow-up is ongoing. Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survival benefit observed with tafa-len-R-CHOP. Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL. Funding Incyte Corporation.